The overall objective of this Program Project Grant continues to be the definition of determinants and the elucidation of mechanisms responsible for the interindividual variability in response following drug administration in humans. The basic and clinical knowledge derived from the proposed research will provide a basis for the rational development and safe use of drugs. The Program's goals will be achieved by a group of investigators with expertise and interests in medicine, pharmacology, biochemistry, molecular biology, genetics and analytical/organic chemistry. The important of racial/ethnic origin in d rug disposition and pharmacological effects is emerging as an important factor in drug evaluation and clinical use, because of the increasing diversity of the U.S. population and the global nature of drug development and marketing. Studies are proposed to investigate inter-racial differences in drug metabolism between Caucasians, African- Americans, Japanese, Mexican-Americans, and Asian-Indians using probe drugs to estimate the in vivo activities of cytochrome P450s, CYP2E1, CYP3A, CYP2D6 and CYP2C19. Factors which modulate the first-pass metabolism of drugs and the activation of environmental procarcinogens will be investigated with a focus on diet and disease states. The importance of various dietary factors in CYP2E1- and CYP3A-mediated metabolism will be studies, as well as the functioning of the intestinal P-glycoprotein efflux pump. The effect of intestinal inflammation caused by celiac disease and tropical sprue on oral bioavailability will also be studied.